Hepatocellular carcinoma (HCC) is one of the most common cancers in the world and the third leading cause of cancer deaths. HCC has a high mortality rate with a five-year survival rate of less than 5percent, with or without therapeutic interventions. The infection by hepatitis B virus (HBV) and hepatitis C virus (HCV) accounts for 75-85 percent of the HCC cases. The goal of this Program Project Grant (PPG) application is to investigate how HBV and HCV induce HCC and the host genetic factors that may be involved in these oncogenic processes. In addition, we will also explore novel therapeutic options for the treatment of HCC patients. There are four component projects and one Administrative Core in this PPG. The Administrative Core will be responsible for the administrative and budgetary issues and the four component projects are to study: Project 1: Transgenic mice as a model system for HBV replication and oncogenesis Project 2: Hepatic carcinogenesis induced by hepatitis B virus preS2 mutant Project 3: Hepatocarcinogenesis and skin disease by c-jun/Stat3 and repair deficiency in HCV Project 4: SAMe: a novel therapy for hepatocellular cancer The first three projects use animals and cell cultures as model systems to study how HBV and HCV cause HCC. The fourth project focuses on human subjects to study host genetic factors and therapeutic options. These component projects complement one another. Their research interactions will create a productive synergism that will generate research results for the comprehensive understanding of the molecular etiology of HCC and for the possible development of novel therapeutic options for HCC patients.